A comprehensive study to delineate the role of an extracellular vesicle‐associated microRNA‐29a in chronic methamphetamine use disorder

Abstract

Extracellular vesicles (EVs), which express a repertoire of cargo molecules (cf. proteins, microRNA, lipids, etc.), have been garnering a prominent role in the modulation of several cellular processes. Here, using both non‐human primate and rodent model systems, we provide evidence that brain‐derived EV (BDE) miRNA, miR‐29a‐3p (mir‐29a), is significantly increased during chronic methamphetamine (MA) exposure. Further, miR‐29a levels show significant increase both with drug‐seeking and reinstatement in a rat MA self‐administration model. We also show that EV‐associated miR‐29a is enriched in EV pool comprising of small EVs and exomeres and further plays a critical role in MA‐induced inflammation and synaptodendritic damage. Furthermore, treatment with the anti‐inflammatory drug ibudilast (AV411), which is known to reduce MA relapse, decreased the expression of miR‐29a and subsequently attenuated inflammation and rescued synaptodendritic injury. Finally, using plasma from MUD subjects, we provide translational evidence that EV‐miR29a could potentially serve as a biomarker to detect neuronal damage in humans diagnosed with MA use disorder (MUD). In summary, our work suggests that EV‐associated miR‐29a‐3p plays a crucial role in MUD and might be used as a potential blood‐based biomarker for detecting chronic inflammation and synaptic damage.

Methamphetamine Induces the Release of Proadhesive Extracellular Vesicles and Promotes Syncytia Formation: A Potential Role in HIV-1 Neuropathogenesis

“…A previous study showed that HIV infection increases EV release in microglia [ 49 ]. We have previously demonstrated that meth increases EV releases in animal (rat and monkey brain tissues) and cell culture models [ 50 ]. However, the effects of meth on EV release in HIV infected cells have not been investigated.…”

“…Intriguingly, in uninfected U937 cells, meth did not increase the concentration of large 10 K particles when compared to the smaller 100 K particles ( Figure 1 B,C). In our recent study, we showed that meth increases EV biogenesis in uninfected microglial cells, however, it increased specifically smaller sized particles when compared to larger sized particles [ 50 ]. This could be the same in uninfected U937 cells as well.…”

“…EVs can activate microglia [ 85 , 86 ] and activation of microglia correlates with HAND in clinical settings [ 87 ]. Meth increases EVs biogenesis in the brain [ 50 ], and through direct and indirect mechanisms, it exacerbates the severity and onset of HAND [ 88 ]. Various studies have demonstrated that HIV proteins are released in EVs [ 63 , 64 , 65 ].…”

“…Here, we investigated the role of 10 K and 100 K EVs in HIV neuropathogenesis. We have previously reported that EVs from the brain of meth-treated monkeys showed significant heterogeneity in size and higher concentrations than control animals [ 50 ]. However, a comprehensive study investigating the impact of different types of EVs, such as exosome, microvesicle, mitovesicle, apoptotic EVs, exomere, or low and high-density EVs might be necessary to decipher the role of EVs heterogeneity in HIV pathogenesis.…”

Decoding the Synaptic Proteome with Long-Term Exposure to Midazolam during Early Development

“…Western blotting was performed as described in our previous studies [51,56,59]. Briefly, purified synaptosomes (7.5 µg) from each animal from the two groups were loaded onto 10% Bis-Tris wells (Invitrogen, Waltham, MA, USA) under reducing conditions, followed by transfer to a nitrocellulose membrane using iBlot2 (Invitrogen, Waltham, MA, USA) and immunodetection.…”